The role of thalamic dopamine D2 Receptors in cocaine intake Dopamine D2 receptors (D2Rs) in the ventral striatum have been linked to cocaine abuse, treatment response and relapse in humans, but knowledge about the mechanisms by which D2Rs regulate cocaine intake is still limited. The role of D2Rs in drug abuse has been extensively studied in the nucleus accumbens (NAc). In contrast, the involvement of thalamic receptors in addiction has been largely ignored, most likely due to the relatively sparse dopaminergic innervation and DA receptor expression in the thalamus. Our preliminary data, however, show significant expression of functional D2Rs in the paraventricular nucleus of the thalamus (PVT). Using genetic tools we were able to target D2R-positive neurons in the PVT and we identified prominent projections to the NAc, which is a key brain region involved in drug addiction. Moreover, in line with a role of PVT-D2Rs in cocaine mediated behaviors, we observed that upregulation of D2Rs in the PVT attenuates cocaine sensitization. Based on our preliminary data and published evidence supporting a role of the PVT in drug abuse we propose here the novel idea that thalamic D2Rs regulate cocaine reinforcement and seeking. The immediate goal of this R21 application is to determine whether PVT D2Rs regulate cocaine self- administration. The long term goal is to identify mechanisms by which PVT D2Rs modulate the effects of cocaine on circuit function and behavior. DA innervation and DA transporter (DAT) density are scarce within the PVT, whereas both are high in the NAc shell. We therefore hypothesize that presynaptic D2Rs on PVT terminals within the NAc are better positioned to mediate the actions of cocaine-induced DA release. In a first step, we will test this idea and determine whether presynaptic D2Rs indeed modulate transmission at PVT-to- NAc synapses and whether this modulation affects DA release. Aim 1: To determine whether PVT-D2Rs regulate cocaine self-administration Aim 2: To determine whether PVT-D2Rs modulate PVT to NAc synaptic transmission and DA release These studies are a first step in understanding the role of thalamic D2Rs in cocaine abuse. Future studies will expand the mechanistic analysis to determine whether repeated cocaine self-administration induces alterations in striatal circuit function via PVT-D2Rs. Understanding the mechanistic relationship between D2Rs and cocaine intake is important since multiple brain imaging studies in humans have associated alterations in D2Rs levels with cocaine abuse, treatment response and relapse.